We hypothesized that current use of SSRI would increase the risk of re-operation after breast cancer surgery due to postoperative bleeding, and the results of this investigation were consistent with that hypothesis. While current users of SSRI had almost tripled the risk of re-operation due to postoperative bleeding, the absolute change in risk was only from 2.7% to 7.0%.
The present study is population-based with complete prescription and follow-up data. Recall-bias was eliminated by use of prescription records generated before the initial breast cancer surgery date and all data were obtained prospectively from population-based registries that have a completeness approaching 100% . This information was linked together by the unique CPR number  that has been used productively for research housed in the Danish registries for 15 years [16, 17].
Our comparison of post-surgical bleeding risk in SSRI users versus never SSRI users may raise a concern about non-comparability of the baseline risk of post-surgical bleeding related to indications for SSRI use. For example, patients with a history of depression, which is the primary indication for SSRI use, may tend to have a less healthy lifestyle than patients without a history of depression with respect to tobacco use, diet, alcohol use, and exercise [18, 19]. Depressed patients may also more often use pain medications, such as NSAID, which are known to impair platelet aggregation and thus increase risk of bleeding. This non-comparability of baseline risks would lead to an overestimation of the effect of SSRI use on the risk of re-operation. We controlled confounding by the most frequently used drugs and comorbid diseases related to coagulation and bleeding, and this control had little impact on the estimates of association. However, we were unable to control for NSAIDs bought over the counter or alcohol consumption, as we have no reliable registry data on these habits.
A limitation of the current study is that it includes no information on SSRI prescription compliance. For example, women defined as current users may not have taken the medication up to the day of surgery. Our information on SSRI use relied on registration of dispensed prescriptions and the Danish health care system covers only a proportion of the costs of prescribed medicine. Dispensed prescriptions for which patients must pay part of the cost are likely to be actually used. Furthermore, women on anti-depressant medication with the additional distress of a newly diagnosed breast cancer would be unlikely to stop their anti-depressant medication. Earlier studies on orthopaedic surgery and coronary artery bypass surgery [5, 6], have used the requirement of blood transfusion as a proxy for peri-operative bleeding when investigating its association with SSRI use. We used re-operation due to post surgical bleeding, because peri-operative bleeding in the case of breast cancer surgery rarely results in blood transfusion. In addition, registration of re-operation due to post surgical bleeding in the Danish National Registry of Patients is virtually complete [20–22].
The overall risk of re-operation due to postoperative bleeding in breast cancer patients observed in our study was of the same magnitude as that observed in a small single centre cohort (0.8-4.1%) , which adds further support to the validity of our outcome measure.
The clinical relevance of SSRI in relation to bleeding has been discussed for almost two decades [1, 2, 23]. Breast cancer surgery is a soft tissue surface-surgery often characterised by extensive dissection, which increases the risk of postoperative bleeding compared with many other surgical soft tissue procedures. As we found an increased risk of re-operation due to post-surgical bleeding associated with current use of SSRI, our findings may also be relevant to other soft-tissue surgical procedures of similar character where bleeding might have more fatal consequences.
Our results show overall low risk of re-operation due to post-surgical bleeding among breast cancer patients regardless of whether they are current, former, or never users of SSRI medications. The consequence of stopping SSRI medication used to treat depression in women undergoing treatment for breast cancer may be overwhelming, and may even delay any subsequent cancer-directed treatment. Thus, the potential consequences of stopping the treatment -- taken together with the low overall risk -- suggests that physicians and patients should discuss the risks and benefits of discontinuing treatment with SSRI before breast cancer surgery.